EP4123033A1 - Blutmatrix als referenzmaterial für die in-vitro diagnostik - Google Patents
Blutmatrix als referenzmaterial für die in-vitro diagnostik Download PDFInfo
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- EP4123033A1 EP4123033A1 EP21187066.2A EP21187066A EP4123033A1 EP 4123033 A1 EP4123033 A1 EP 4123033A1 EP 21187066 A EP21187066 A EP 21187066A EP 4123033 A1 EP4123033 A1 EP 4123033A1
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- blood
- cells
- reference material
- tumor
- dna
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6806—Preparing nucleic acids for analysis, e.g. for polymerase chain reaction [PCR] assay
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6844—Nucleic acid amplification reactions
- C12Q1/686—Polymerase chain reaction [PCR]
Definitions
- the present invention relates both to a new reference material based on a blood matrix for use in diagnostics or in vitro diagnostics, in particular those using sequencing methods of nucleic acids such as polymerase chain reaction (PCR) or next generation sequencing (NGS). also a method for its production including validation, in particular a non-invasive liquid biopsy (liquid biopsies).
- PCR polymerase chain reaction
- NGS next generation sequencing
- tumor markers in particular oncogenes, have been determined in body fluids such as blood, urine, sputum or tissue samples. These are components of Tumor cells that are formed more or less and whose changes can be detected in body fluids such as blood, plasma or serum.
- nucleic acids ribonucleic acids, RNA and deoxyribonucleic acids, DNA
- PCR polymerase chain reaction
- such cell material is provided for diagnostics in the following steps, such as sample preparation, extraction, concentration, isolation, purification, reverse transcription, if necessary, amplification and detection.
- the documentation of the clinical validity of a test also includes the evaluation of the analytical validity, which is described by the parameters accuracy, sensitivity, specificity and robustness of the test.
- the pre-analytical variables have a great influence on these parameters, which are factors without direct association with the disease, but which affect the integrity of the body fluid or the biomarker (analyte) present in this body fluid or influence the results during the analysis and technical, biological or environmental origin. In the field of liquid biopsy tests, these are e.g. the extraction and quantification method used, storage conditions, PCR inhibition and fragment size bias. These pre-analytical variables can consequently lead to inter-laboratory variability.
- qPCR real-time quantitative polymerase chain reaction
- ddPCR digital droplet PCR
- NGS next generation sequencing
- massive Parallel Sequencing the so-called non-invasive liquid biopsy has been established in tumor diagnostics in recent years, whereby, for example, circulating free DNA in a sample is examined.
- circulating free DNA cfDNA for short
- the average cfDNA amount is higher than in healthy subjects, in particular, the cfDNA plasma level is higher in advanced-stage cancer patients than in mild/early-stage cancer patients.
- ctDNA makes up 1% of cfDNA (0.01-90% of normal cfDNA, depending on the stage and location of the tumor).
- test material e.g. blood, tissue, spinal fluid, mucosal swabs, sputum, urine, semen, saliva, or other types of samples.
- the reference materials should have comparable physical and biological properties to the sample or starting material used. This in turn means that the focus is not only on the properties of the biomarker, but also on the sample matrix, which can contain a biomarker/analyte to be detected, for example.
- the target molecule of the liquid biopsy test eg ct/cfDNA (circular tumor/cell free) is found in the blood as cell-free DNA and is isolated from the blood taken after blood has been taken, plasma is subsequently generated and DNA is extracted.
- a blood sample as reference material which largely corresponds to an original blood sample or sufficiently simulates it so that such a reference material can be compared with a patient blood (plasma, serum) sample.
- the patient's blood sample can have been treated in any way.
- the object of the present invention is therefore to provide an improved method for carrying out diagnostics or in-vitro diagnostics, blood being used to achieve this object or, in one of the following embodiments, being used as reference material.
- the invention therefore relates to the use of i.) blood or ii.) blood cells and blood plasma or blood serum as reference material in a sample in diagnostics or in-vitro diagnostics comprising a sequencing method of nucleic acids, with a stabilizer being added if necessary.
- the stabilizer is to be chosen in such a way that there is no influence on the biomarker or analyte to be determined.
- the invention relates to the use of a reference material comprising blood in a sample in an in-vitro diagnosis comprising a sequencing method of nucleic acids, blood plasma or blood serum being added to blood cells.
- the invention relates to a method for producing blood as a reference material in a sample in in-vitro diagnostics, comprising a sequencing method for nucleic acids, blood plasma or blood serum being added to blood cells, and preferably one or more stabilizers being added.
- Such stabilizers suitable according to the invention are preferably selected from the groups such as crosslinking stabilizers, alcoholic stabilizers and/or anticoagulants.
- crosslinking stabilizers such as crosslinking stabilizers, alcoholic stabilizers and/or anticoagulants.
- Formaldehyde, glutaraldehyde, glyoxal and acrolein, or mixtures thereof, are particularly preferred.
- Such stabilizers can also be used, such as crosslinking stabilizers which produce covalent chemical bonds between proteins, such as, but not limited to, selected from the group of formaldehyde, paraformaldehyde, formalin, glutaraldehyde, osmium tetraoxide, imidoester crosslinkers such as dimethyl suberimidate (DMS), acrolein , glyoxal, carbodiimides, or alcoholic stabilizers such as, but not limited to, selected from the group of ethanol, methanol, acetone, acetic acid, 2-phenoxyethanol, diethyl ether or anticoagulants/chelating agents such as, but not limited to, selected from the group EDTA (ethylenediaminetetraacetic acid), Heparins and heparinoids, citrate, dimercaptosuccinic acid, dimercaptopropanesulfonic acid, acid citrate dextrose, acetylacetone, ethylenediamine,
- the invention relates to such blood plasma or blood serum which is not provided from humans or animals, but largely corresponds to a composition of blood components, with the individual blood components being added in each case.
- a reference material according to the invention can therefore have the following composition for the blood serum or blood plasma, as shown in Table 1, with serum or plasma proteins, in particular albumin, one or more blood components being added, in particular up to 5 components or 10 components or 20 components or 30 Constituents from Table 1 .
- up to 76 components from Table 1 can be added in addition to albumin.
- the concentrations of the selected components may vary in each case, or be selected from Table 1 in each case.
- Table 1 Reference values for relevant blood components in plasma/serum according to Hahn, Internal Medicine Checklist, 2006 Substance name / blood component Preferred Concentrations 1. ACTH 2-11 pmol/L 2. albumin 35-55 g/l 3. alpha amylase ⁇ 100U/L 4.
- Alpha-Fetoprotein (AFP) ⁇ 10ng/mL 5.
- antistreptolysin titer ⁇ 200 IU/mL 8th.
- Antithrombin (AT III) 75-120% 9.
- total bilirubin 3.4-18.8 ⁇ mol/l 10 bilirubin directly 0.9-5.1 ⁇ mol/l 11.
- bilirubin indirectly ⁇ 13.7 ⁇ mol/L 12.
- the composition is free from antibodies, in particular free from immunoglobulins and/or free from DNA, RNA or extracellular vesicles.
- Such a provided blood sample is referred to below as reference material according to the invention.
- the added blood plasma or blood serum has defined values for at least one ingredient selected from the group gDNA, fragmented DNA, tumor-associated and non-tumor-associated, methylated or non-methylated cfDNA, histone-bound DNA, circular DNA, mitochondrial DNA, single-stranded or double-stranded DNA, ctDNA, RNA, methylated or non-methylated RNA, miRMA, tRNA, scRNA, rRNA, mRNA, tumor nucleic acid, spiked nucleic acid, exosome, proteins, peptides, extracellular vesicles, exosomes, especially with the following ranges 1-1500 ng DNA/ ml, especially with a proportion of cfDNA in pregnant women of 2-15% of fetal cfDNA, 1-1000 ng RNA/ml.
- the added blood plasma or blood serum has defined levels of at least one biological material selected from the group consisting of cells, eukaryotic cells, viruses, fungi, fungal spores, prions, bacteria, parasites, tumor cells, circulating tumor cells (CTC), circulating endothelial cells (CTEC), in particular with the following ranges 1-100,000 viruses/ml, 1-100,000 bacteria/ml, 1-100,000 fungi/ml, 1-100,000 fungal spores/ml, 1-100,000 parasites/ml, 1-1,000 tumor cells/ml or 1-1,000 endothelial cells/ml.
- CTC circulating tumor cells
- CTEC circulating endothelial cells
- the aforementioned embodiments of the reference material according to the invention advantageously allow the simulation of blood samples from, for example, sick patients and other conditions.
- fragmented (cell-free) DNA which can occur in different sizes, preferably in the size ranges 140-180 base pairs (bp), 310-350 bp, 480-520 bp, is used.
- the inventors were able to establish that the size as well as the size distribution of such cfDNA in a reference material is critical for sequencing methods of nucleic acids.
- large cfDNA fragments can be used, preferably in the range of 2,000 to 15,000 bp, while mitochondrial DNA between 40-300 bp is used.
- Extrachromosomal circular DNA ranges in size from 30-20,000 bp.
- RNA in particular miRNA, which can occur in different sizes, preferably in the size ranges 10-250 bp, in particular 10-500 bp, is used.
- the inventors were able to determine that just for Sequencing of nucleic acids, the size and size distribution of such RNA, especially miRNA in a reference material is critical.
- Blood within the meaning of this invention can be whole blood which has blood cells and blood serum.
- the blood can be taken from a human or an animal.
- blood cells are those which remain in the residue after the blood serum has been separated off, for example after centrifugation, and include erythrocytes, leukocytes, thrombocytes and the like.
- the proportion of blood cells is 15-70% by weight, preferably 37-54% by weight, of the reference material according to the invention.
- erythrocytes 4.5-5.9 ⁇ 10 6 cells/ ⁇ l of blood, with the lowest value for women and the highest value for men.
- ⁇ 1% leukocytes approximately 4,000-10,000 cells/ ⁇ l blood for adults and for children: up to 17,000 cells/ ⁇ l blood, infants up to 30,000 cells/ ⁇ l blood
- ⁇ 1% Platelets approximately 150,000 - 400,000 cells/ ⁇ l blood
- Blood plasma within the meaning of this invention can be obtained by centrifuging blood and separating off the supernatant, the blood having previously been treated with an anticoagulant such as sodium citrate or EDTA.
- the blood plasma usually contains all coagulation and fibrinolysis factors in active form, as well as the cfDNA, which particularly in the application of liquid biopsy testing.
- Blood serum within the meaning of this invention can be obtained by centrifuging blood and separating off the supernatant. In contrast to blood plasma, it does not contain any anticoagulants.
- Blood serum or blood plasma can also be used for the purposes of this invention, in particular those which essentially have the following components: Table 2: Example of a composition and concentrations of the ingredients of a serum or plasma according to the invention (solvent is water) Substance name / blood component concentration Plasma proteins, especially albumin 50.3 g/l Electrolytes (Na + ) 89.6 mmol/L Electrolytes (K + ) 2.0 mmol/L Electrolytes (Ca + ) 0.025mmol/L Electrolytes (Cl - ) 105.8 mmol/L Electrolytes (PO 4 3- ) 6.7 mmol/L substance name concentration Plasma proteins, especially albumin 50.3 g/l Electrolytes (Na + ) 89.6 mmol/L Electrolytes (K + ) 2.0 mmol/L Electrolytes (Ca + ) 0.025mmol/L Electrolytes (Cl - ) 105.8 mmol/L Electrolytes (PO 4 3- ) 6.7
- one or more chemical substances can therefore be added to the reference material according to the invention.
- Such chemical substances cannot be exhaustive, in particular at least one organic molecule which, in addition to carbon (C) and hydrogen (H), can contain heteroatoms such as oxygen (O), nitrogen (N), sulfur (S) or phosphorus (P).
- the chemical substances can have linear and/or ring-shaped carbon chains including heteroatoms. Organic molecules with less than 1000 g/mol are preferred.
- Such a chemical substance can be a biomarker, analyte, drug, antibody, antigen or drug.
- an ingredient can be added, selected from the group gDNA, fragmented DNA, tumor-associated and non-tumor-associated, methylated or non-methylated cfDNA, histone-bound DNA, circular DNA, mitochondrial DNA, single-stranded or double-stranded DNA, ctDNA, RNA, methylated or non-methylated RNA, miRMA, tRNA, scRNA, rRNA, mRNA, Tumor nucleic acid, spiked nucleic acid, exosome, proteins, peptides, extracellular vesicles, exosomes.
- one or more biological materials can be added to the reference material according to the invention, such as cells, eukaryotic cells, viruses, fungi, fungal spores, prions, bacteria, parasites, tumor cells, circulating tumor cells (CTC ), circulating endothelial cells (CTEC).
- biological materials such as cells, eukaryotic cells, viruses, fungi, fungal spores, prions, bacteria, parasites, tumor cells, circulating tumor cells (CTC ), circulating endothelial cells (CTEC).
- the content of a tumor nucleic acid is preferably 5-1000 ng, in particular 400 ng DNA in serum or plasma, such as 400 ng/5ml, corresponds to 80 ng/ml, corresponds to 0.08 ng/ ⁇ l DNA in serum or Plasma.
- the tumor nucleic acid has a size of 30 bp to 500 bp.
- spikeked nucleic acid means a sequence that has one or more mutations compared to a human wild-type sequence of a nucleic acid.
- known mutation sequences compared to the human wild-type sequence can be used or artificial mutations can be introduced.
- the spiked nucleic acid has at least one tumor marker, eg oncogene, with known mutations, in particular an oncogene selected from the group ABI1,ABL1,ABL2,ACKR3,ACSL3,ACVR1,ACVR2A,AFDN,AFF1,AFF3,AFF4,AK T1,AKT2,ALK,AMER1,APC,APOBEC3B,AR,ARHGAP26,ARHGEF12,ARID1A,ARI D1B,ARID2,ARNT,ASPSCR1,ASXL1,ATF1,ATIC,ATM,ATP1A1,ATP2B3,ATR,A TRX,AXIN1,AXIN2, B2M,BAP1,BARD1,BAX,BCL10,BCL11A,BCL11B,BCL2,BC L3,BCL6,BCL7A,BCL9,BCL9L,BCOR,BCORL1,BCR,BIRC3,BLM,BMPR1A,BRAF ,BRCA1,BRCA2,BRD3,BRD4,
- tumor marker sequences or oncogenes can have further artificial mutations.
- validation means that the intended diagnosis or in-vitro diagnosis is carried out using the reference material according to the invention as a reference sample, in particular to carry out a calibration taking into account the device parameters or to create a calibration curve.
- the in-vitro diagnosis is a liquid biopsy, with a blood sample being measured against the blood sample according to the invention or the blood sample according to the invention preferably by means of PCR used for calibration, validation, diagnostics or in-vitro diagnostics.
- sample nucleic acid e.g. from a blood sample
- sample nucleic acid can advantageously be detected in this way with sufficient specificity and sensitivity to the reference material according to the invention.
- this particularly advantageously allows an early statement to be made about the tumor activity, in particular the probability of metastasis.
- a preferred sample nucleic acid is cfDNA or ctDNA from a patient or subject.
- the invention therefore also relates to the advantageous use of the reference material in a method for determining the allele frequency and/or mutation rate and/or for absolute quantification by determining the copy number of at least one sample nucleic acid using a sequencing method for nucleic acids.
- a quantitative determination of the sample nucleic acid can be carried out particularly advantageously on the basis of the calibration or validation.
- the invention relates to the advantageous use of the reference material in a method for pre-analytical evaluation (transport, processing of a blood sample, storage / repeated use, e.g. freeze / thaw cycles, extraction process), analytical evaluation (accuracy / precision, repeatability / reproducibility, analytical specificity / sensitivity , limit of detection, limit of quantification, limit of blank, linearity, interference, robustness).
- a particularly advantageous application therefore relates to the validation of devices for carrying out a polymerase chain reaction (PCR), in particular next generation sequencing (NGS).
- PCR polymerase chain reaction
- NGS next generation sequencing
- an exactly predetermined amount of DNA material or concentration can be introduced into the reference material according to the invention, with this reference material simulating a patient's blood sample and being particularly suitable for carrying out tumor diagnostics, pregnancy diagnostics, hereditary genetic diagnostics or infection diagnostics.
- In vitro diagnosis within the meaning of this invention means any diagnosis outside of the human or animal body (ex vivo) with the provision of suitable assays and devices. The statement about a disease or a condition of a patient is preferred.
- patient is understood to mean any subject.
- the individual components from Table 1 can be mixed with blood cells and in this way a suitable reference material can be provided.
- Added DNA in the reference material can be added fragmented as follows, among other things, in order to be able to depict the biological situation of a person as closely as possible.
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Abstract
Die vorliegende Erfindung betrifft sowohl ein neues Referenzmaterial auf Basis einer Blutmatrix zur Verwendung in der Diagnostik, bzw. in-vitro Diagnostik, insbesondere solche mithilfe von Sequenzierverfahren von Nukleinsäuren, wie Polymerase-Chain-Reaction (PCR) oder Next Generation Sequencing (NGS) als auch ein Verfahren zu dessen Herstellung samt Validierung, insbesondere einer nicht-invasiven Liquid Biopsy (Flüssigkeitsbiopsien).
Description
- Die vorliegende Erfindung betrifft sowohl ein neues Referenzmaterial auf Basis einer Blutmatrix zur Verwendung in der Diagnostik, bzw. in-vitro Diagnostik, insbesondere solche mithilfe von Sequenzierverfahren von Nukleinsäuren, wie Polymerase-Chain-Reaction (PCR) oder Next Generation Sequencing (NGS) als auch ein Verfahren zu dessen Herstellung samt Validierung, insbesondere einer nicht-invasiven Liquid Biopsy (Flüssigkeitsbiopsien).
- Gegenwärtige Verfahren zum Nachweis von Tumoren wie klinischchemische Untersuchungen in Körperflüssigkeiten und Gewebeproben oder bildgebende Verfahren führen trotz aller Fortschritte in den letzten Jahren zu einem meist zu späten Nachweis von malignen Veränderungen. So ist die Hauptursache der hohen Mortalitätsrate von Tumorpatienten nicht das Auftreten von Primärtumoren, sondern von Metastasen. Um das Auftreten von Metastasen zu verhindern, ist ein so früh wie möglicher Nachweis von malignen Veränderungen erforderlich. Ferner bedarf es Verfahren, um maligne Zellen von normalen Zellen richtig unterscheiden zu können. Sowohl falsch-positive als auch falsch-negative Befunde haben fatale Konsequenzen für die Betroffenen. Ebenso sind Verfahren erforderlich, die eine richtige Prognose von Tumorpatienten gestatten und eine entsprechend auf den Patienten individuell abgestimmte Therapie erlauben.
- Bisher werden in Körperflüssigkeiten wie Blut-, Urin-, Sputum- oder Gewebeproben sogenannte Tumormarker, insbesondere Onkogene bestimmt. Hierbei handelt es sich um Bestandteile von Tumorzellen, die verstärkt oder vermindert gebildet werden und deren Veränderungen in Körperflüssigkeiten wie Blut, Plasma oder Serum nachgewiesen werden können.
- Die Isolierung, Charakterisierung und Analyse intrazellulärer Bestandteile, vor allem von Nukleinsäuren (Ribonukleinsäuren, RNA und Desoxyribonukleinsäuren, DNA), ist von großer Bedeutung für die moderne Molekularbiologie. Spätestens seit der Erfindung der Polymerasekettenreaktion (PCR) im Jahre 1983 ist eine Vielzahl von Nukleinsäurediagnostik-Verfahren entwickelt worden, die beispielsweise zum Nachweis von Krankheiten und Krankheitserregern genutzt werden.
- Im Stand der Technik wird solches Zellmaterial in den nachfolgenden Schritten, wie Probenaufbereitung, Extraktion, Konzentration, Isolierung, Reinigung, ggfs. reverse Transkription, Amplifikation und Detektion für die Diagnostik bereitgestellt.
- Die Analyse genetischer Krebsveränderungen ist heutzutage von zentraler Bedeutung für das Patientenmanagement und die Therapieentscheidung. Die Bewertung des Mutationsprofils im Rahmen einer Krebserkrankung erfolgt meistens durch den Einsatz genetischer Tests. Dabei hat die Anwendung von Flüssigkeitsbiopsien aus Blut, die sich auf die Analyse der zirkulierenden Tumor-DNA (ctDNA), bzw. zellfreie DNA (cell free, cfDNA), oder RNA, z.B. solche in Exosomen oder zirkulierenden Tumorzellen (CTC, circulating tumour cells) bezieht, in den letzten Jahren in der klinischen Praxis enorm zugenommen, da sie eine kontinuierliche, minimal-invasive Überwachung des Tumorgenoms über den Krankheitsverlauf erlaubt. Mit der Verbreitung solcher Tests spezifisch für Flüssigkeitsbiopsien und ihrer Anwendung in der Routinediagnostik und wachsenden regulatorischen Anforderungen steigt gleichzeitig auch die Notwendigkeit, dass Assays validiert und nach gleichwertigen Standards durchgeführt werden.
- Die Dokumentation der klinischen Validität eines Tests umfasst auch die Bewertung der analytischen Validität, welche durch die Parameter Genauigkeit, Sensitivität, Spezifität und Robustheit des Tests beschrieben werden. Einen großen Einfluss auf diese Parameter haben die prä-analytischen Variablen (bzw. Prozesse), welche Faktoren ohne direkte Krankheitsassoziation, aber sich auf die Integrität der Körperflüssigkeit oder des in dieser Körperflüssigkeit vorhandenen Biomarkers (Analyten) auswirken oder die Ergebnisse während der Analyse beeinflussen und technischen, biologischen oder umweltbedingten Ursprungs sein können. Im Bereich der Flüssigkeitsbiopsietests sind das z.B. die verwendete Extraktions- und Quantifizierungsmethode, Lagerungsbedingungen, PCR-Inhibition und Fragmentgrößenbias. Diese prä-analytischen Variablen können folglich zu Abweichungen zwischen den Laboren führen.
- Aufgrund der leistungsfähigen Amplifikation von Tumor-DNA mittels Sequenzierverfahren von Nukleinsäuren, insbesondere PCR, "qPCR" (real-time quantitative Polymerase Chain Reaction), "digital droplet PCR" (ddPCR), oder "next generation sequencing" (NGS, bzw. Parallelsequenzierung wie "Massive Parallel Sequencing") ist in den letzten Jahren die so genannte nicht-invasive Liquid Biopsy in der Tumordiagnostik etabliert worden, wobei zum Beispiel zirkulierende freie DNA in einer Probe untersucht wird. Solche zirkulierende freie DNA (kurz: cfDNA) kann beispielsweise aus einer Krebs-/Tumorzelle stammen (so genannte: ctDNA).
- Bei Krebspatienten liegt die durchschnittliche cfDNA Menge höher als in gesunden Probanden, insbesondere ist das cfDNA Plasma Level bei Krebspatienten im fortgeschrittenen Stadium höher als im milden/frühen Stadium. ctDNA macht z.B. 1% der cfDNA aus (0,01-90% der normalen cfDNA, je nach Stadium und Lokalisation des Tumors).
- Es besteht jedoch ein hohes Bedürfnis an einem Standard, so dass nicht nur relative, sondern auch absolute diagnostische Aussagen getroffen werden können. Der Einsatz eines solchen Standards wird zum Beispiel in
WO2018094183A1 oderPCT/EP2021/050962 - Derzeit stehen z.B. für Mutationen, die es für die Tumordiagnostik nachzuweisen gilt, sowohl kommerzielle Tests als auch Laboreigene Tests (lab-developed test, LDT) zur Verfügung. Als Qualitätskontrollen für die Validierung bzw. Kalibrierung werden Labor-interne Standards wie z.B. Plasmid-DNA oder synthetische Oligonukleotide u.v.a. eingesetzt.
- Von besonderem Nachteil ist, dass diese Labor-internen Standards die tatsächlichen Eigenschaften der aus Menschen oder Tieren erhaltenen Proben samt enthaltenen Biomarker oder Analyten oft ungenügend abbilden. Eine solche Probe betrifft das Untersuchungsmaterial wie es an einem Labor erhalten wird, also z.B. Blut, Gewebe, Rückenmarksflüssigkeit, Schleimhautabstriche, Sputum, Urin, Samen, Speichel, oder sonstige Probenarten.
- Nachteilig ist ebenfalls, dass diese Labor-internen Standards zwecks Validierung oder Kalibrierung eines Gerätes oder eines Verfahrens in der in-vitro Diagnostik selbst verdünnt werden müssen und hierfür kein automatisierter Prozess zur Verfügung steht, sodass eine Standardisierung zumeist fehlerbehaftet ist. Ferner ist die Stabilität solcher Verdünnungen nicht gewährleistet und je nach Quelle wie z.B. Plasmid-DNA aus E. coli besteht die Gefahr einer DNA/RNA-Kontamination durch diese nicht humane oder nicht tierische Spezies, wobei bereits minimale Einträge kritisch sind. Folglich kann zum Beispiel die mittels PCR oder NGS ermittelte Kopienzahl mangels hinreichender Standardisierung relativ und absolut falsch sein.
- Es ist offensichtlich, dass zur Bestimmung, Bewertung und Nachverfolgung der Analyseleistung, sowie zur Qualitätsüberwachung von Laboren interne und externe Kontrollen in Form eines Referenzmaterials erforderlich sind. Dabei sollen die Referenzmaterialien vergleichbare physikalische und biologische Eigenschaften zum eingesetzten Proben- bzw. Ausgangsmaterials aufweisen. Das wiederum bedeutet, dass nicht nur ein Fokus auf die Eigenschaft des Biomarkers gelegt wird, sondern eben auf die Probenmatrix, in der sich zum Beispiel ein nachzuweisender Biomarker/Analyt befinden kann. Das Zielmolekül der Flüssigkeitsbiopsietests, z.B. ct/cfDNA (circular tumor /cell free) befindet sich als zellfreie DNA im Blut und wird nach Blutabnahme, anschließender Plasma-Generierung aus dem abgenommenen Blut und mittels DNA-Extraktion isoliert. Jedoch nutzen bisherige Referenz- oder Kontrollmaterialien DNA-freies Plasma oder eine DNA-freie Plasma-artige Lösung als Basis, ggfs. weiter mit einem "Biomarker/Analyt of Interest" ergänzt, da Blut als solches zu viele Unbestimmtheiten aufweist. Diese Unbestimmtheiten können erst nach der Extraktion der Unbestimmtheiten analysiert werden. Dies wiederum macht das Blut als Kontrollmaterial unbrauchbar. Solche Unbestimmtheiten können sich aus der Probenbehandlung ergeben (z.B. Einwirkung von Hitze, Verunreinigung, Vollständigkeit, etc.). Als Konsequenz können jedoch die Prozesse der Probenbehandlung (Lagerung) und Plasma-Generierung oder weiterer Aufbereitungsmethoden nachteilig nicht validiert und bewertet werden. Es besteht daher das Bedürfnis eine Blutprobe als Referenzmaterial bereitzustellen, die weitgehend einer originären Blutprobe entspricht oder hinreichend simuliert, so dass ein solches Referenzmaterial mit einer Patienten-Blut(-plasma, -serum)probe verglichen werden kann. Die Patientenblutprobe kann hierbei beliebig behandelt worden sein.
- Daher gilt es und es besteht die Aufgabe, die Standardisierung in der in-vitro Diagnostik, insbesondere solche mittels Sequenzierverfahren von Nukleinsäuren zu verbessern.
- Überraschenderweise konnten die Erfinder feststellen, dass zu einem solchen Standard die Verwendung einer Blutprobe als Referenzmaterial in einer Diagnostik, oder in-vitro Diagnostik, welche ggfs. einen Stabilisator aufweist, die diagnostische Qualität erheblich verbessert, indem durch ein erfindungsgemäßes Referenzmaterial die
- Validität (Eine Messung ist valide, wenn sie tatsächlich das misst, was sie messen soll und somit glaubwürdige Ergebnisse liefert),
- Reliabilität (Die Reliabilität bezieht sich darauf, ob ein Testsystem bei wiederholter Durchführung zuverlässige Ergebnisse liefert), und
- Objektivität (Ein Testsystem ist objektiv, wenn keine ungewollten Einflüsse durch involvierte Personen entstehen) eines gegebenen Testsystems geprüft werden kann. Besonders vorteilhaft können auf diese Weise die Leistungsparameter der Messung überprüft werden. Insbesondere dann, falls eine humane oder tierische, insbesondere von Säugetieren, insbesondere, Rind, Schwein, oder Schaf, Vergleichsblutprobe vorliegt.
- Die Aufgabe wird durch die vermittelte technische Lehre mindestens eines Patentanspruches gelöst.
- Die Aufgabe der vorliegenden Erfindung ist daher die Bereitstellung eines verbesserten Verfahrens zur Durchführung einer Diagnostik, bzw. in-vitro Diagnostik, wobei zur Lösung dieser Aufgabe Blut oder in einer der nachstehenden Ausführungsformen als Referenzmaterial eingesetzt wird.
- Daher betrifft die Erfindung die Verwendung von i.) Blut oder ii.) Blutzellen und Blutplasma oder Blutserum als Referenzmaterial in einer Probe in einer Diagnostik, bzw. in-vitro Diagnostik umfassend ein Sequenzierverfahren von Nukleinsäuren, wobei ggfs. ein Stabilisator hinzugefügt wird. In einer bevorzugten Ausführungsform der Erfindung ist der Stabilisator in der Weise zu wählen, dass kein Einfluss auf den zu bestimmenden Biomarker oder Analyten besteht.
- Weiterhin betrifft die Erfindung die Verwendung eines Referenzmaterials aufweisend Blut in einer Probe in einer in-vitro Diagnostik umfassend ein Sequenzierverfahren von Nukleinsäuren, wobei Blutplasma oder Blutserum zu Blutzellen hinzugegeben wird.
- Zudem betrifft die Erfindung ein Verfahren zur Herstellung von Blut als Referenzmaterial in einer Probe in einer in-vitro Diagnostik umfassend ein Sequenzierverfahren von Nukleinsäuren, wobei Blutplasma oder Blutserum zu Blutzellen hinzugegeben wird, und vorzugsweise ein oder mehrere Stabilisatoren hinzugefügt werden.
- Solche erfindungsgemäß geeigneten Stabilisatoren sind vorzugsweise ausgewählt aus den Gruppen, wie vernetzende Stabilisatoren, alkoholische Stabilisatoren und / oder Antikoagulanzien. Bevorzugt sind insbesondere Formaldehyd, Glutaraldehyd, Glyoxal und Acrolein, oder Mischungen hieraus.
- Weiterhin können solche Stabilisatoren verwendet werden, wie z.B. vernetzende Stabilisatoren, welche kovalente chemische Bindungen zwischen Proteinen herstellen, wie, nicht abschließend, ausgewählt aus der Gruppe Formaldehyd, Paraformaldehyd, Formalin, Glutaraldehyd, Osmiumtetraoxid, Imidoester Crosslinker, wie Dimethyl suberimidate (DMS), Acrolein, Glyoxal, Carbodiimide, oder alkoholische Stabilisatoren, wie, nicht abschließend, ausgewählt aus der Gruppe Ethanol, Methanol, Aceton, Essigsäure, 2-Phenoxyethanol, Diethylether oder Antikoagulazien / Chelatbildner, wie, nicht abschließend, ausgewählt aus der Gruppe EDTA (Ethylendiamintetraessigsäure), Heparine und Heparinoide, Citrat, Dimercaptobernsteinsäure, Dimercaptopropansulfonsäure, Acid-Citrate-Dextrose, Acetylaceton, Ethylendiamin, 2-(2-Aminoethylamino)ethanol, Diethylentriamin, Iminodiacetat, Triethylentetramin, Triaminotriethylamin, Nitrilotriacetat, Bis(salicyliden)ethylendiamin, Ethylendiaminotriacetat, Diethylentriaminpentaacetat, Triethylentetraminhexaacetat, 1,4,7,10-Tetraazacyclododecan-1,4,7,10-tetraacetat, Oxalat, Tartrat, Citrat, Dimethylglyoxim, 8-Hydroxychinolin, 2,2'-Bipyridin, 1,10-Phenanthrolin, 1,2-Bis(diphenylphosphino)ethan, Hirudine und Hirudinanaloga, Apixaban, Edoxaban, Rivaroxaban, Cumarine, Phenprocoumon, Warfarin, Dicumarol, Pentasaccharide, Plättchenaggregationshemmer, Acetylsalicylsäure (ASS), Clopidogrel, Ticagrelor, Prasugrel, GP-IIb-/IIIa-Antagonisten, Tirofiban, Eptifibatid, Bivalirudin, Rivaroxaban, Dabigatran etexilate, Apixaban, PPSB (Prothrombinkomplex), Antithrombin (AT III), Protein C, Desmopressin, DDAVP, Protaminchlorid, Vitamin K, Argatroban, Danaparoid, Danaparin, Lomoparan, oder ausgewählt aus der Gruppe Oxidierende Agenzien, Quecksilber basierte Stabilisatoren, B-5 (Quecksilberchlorid und Natriumacetat in wässriger Lösung), Zenker's Fixativ (Quecksilberchlorid, Kaliumdichromat, Natriumsulfat, Essigsäure, Wasser), Pikrinsäure basierte Stabilisatoren, wie Bouin-Lösung: Pikrinsäure, Essigsäure, Formaldehyd in wässriger Lösung, Ammoniumsulfat in wässriger Lösung, CARNOY Fixierlösung (Chloroform, ggfs. mit Eisen(III)Chlorid oder Formaldehyd-Alkohol-Essigsäure), Chromsäure, Chromessigsäure, Zinksalz Lösung.
- In einer weiteren bevorzugten Ausführungsform betrifft die Erfindung solches Blutplasma oder Blutserum, welches nicht aus Menschen oder Tieren bereitgestellt wird, sondern eine Zusammensetzung aus Blutbestandteilen weitgehend entspricht, wobei die einzelnen Blutbestandteile jeweils hinzugefügt werden.
- Ein erfindungsgemäßes Referenzmaterial kann daher folgende Zusammensetzung für das Blutserum oder Blutplasma aufweisen, wie in Tabelle 1 dargestellt, wobei neben Serum- oder Plasmaproteinen, insbesondere Albumin, ein oder mehrere Blutbestandteile hinzugefügt werden, insbesondere bis zu 5 Bestandteilen oder 10 Bestandteilen oder 20 Bestandteilen oder 30 Bestandteilen aus Tabelle 1. Insbesondere können neben Albumin bis zu 76 Bestandteile aus Tabelle 1 hinzugefügt werden. Die Konzentrationen der ausgewählten Bestandteile können jeweils variieren, oder aus Tabelle 1 jeweils ausgewählt werden.
Tabelle 1: Referenzwerte für relevante Blutbestandteile in Plasma/Serum nach Hahn, Checkliste Innere Medizin, 2006 Stoffname / Blutbestandteil Bevorzugte Konzentrationen 1. ACTH 2-11 pmol/l 2. Albumin 35-55 g/l 3. Alpha-Amylase < 100 U/l 4. Alphal-Fetoprotein (AFP) < 10 ng/ml 5. Alkalische Phosphatase (AP) 65-220 U/l 6. Ammoniak m: 11-55 µmol/l 7. Antistreptolysintiter < 200 IU/ml 8. Antithrombin (AT III) 75-120 % 9. Bilirubin gesamt 3,4-18,8 µmol/l 10. Bilirubin direkt 0,9-5,1 µmol/l 11. Bilirubin indirekt < 13,7 umol/l 12. Calcium 2,3-2,6 mmol/l 13. Carcino-embryonales Antigen (CEA) < 3 mg/l 14. Chlorid 98-112 mmol/l 15. Cholesteringesamt 3,1-6,5 mmol/l 16. HDL > 1,0 mmol/l 17. LDL < 4,0 mmol/l 18. Cholinesterase (CHE) 3000-8000 U/l 19. C3-Komplement 0,55-1,2 g/l 20. C4-Komplement 0,2-0,5 g/l 21. Coeruloplasmin 0,95-3,7 mmol/l 22. C-Peptid 1,1-3,6 mg/l 23. C-reaktives Protein (CRP) < 5 mg/l 24. Creatinkinase (CK) <174 U/l 25. Creatinkinase-Isoenzym MB (CK-MB) < 6 % der CK 26. Digoxin 0,8-2,0 mg/l 27. Digitoxin 15-25 mg/l 28. Eisen 11-27 umol/l 29. alphal-Globulin 1-4 g/l 30. alpha2-Globulin 5-9 g/l 31. beta-Globulin 6-11 g/l 32. gamma-Globulin 8-15 g/l 33. Ferritin 30-200 µg/l 34. Fibrinogen 5,9-11,8 µmol/l 35. Folsäure 3-15 ng/ml 36. Gesamteiweiß 60-84g/l 37. Glukose nüchtern 3,9-5,6mmol/l 38. GGT 4-28 U/l 39. GOT < 18 U/l 40. GPT < 22 U/l 41. Haptoglobin 0,2-2,04g/l 42. Harnsäure 155-384 umol/l 43. Harnstoff 1,7-9,3mmol/l 44. alpha-HBDH 72-182 U/l 45. Immunglobulin G 8-18g/l 46. Immunglobulin A 0,9-4,5g/l 47. Immunglobulin M 0,6-2,6g/l 48. Kalium 3,5-5mmol/l 49. Kalzium 2,3-2,6mmol/l 50. Kreatinin 44-106 µmοl/l 51. Kupfer 11-24 umol/l 52. Laktat 0,63-2,44 mmol/l 53. LDH 135-225 U/l 54. LAP 16-32 U/l 55. Lipase 30-180 U/l 56. Lipoprotein (a) < 300 mg/l 57. Magnesium 0,7-1,6 mmol/l 58. Natrium 135-150 mmol/l 59. Phosphat 0,77-1,55 mmol/l 60. Prostataspez. Antigen < 3 µg/l 61. Rheumafaktor < 20 IU/ml 62. Theophyllin 10-20mg/l 63. TSH basal 0,3-3,5 mU/l 64. freies Thyroxin (FT4) 7-30 pmol/l 65. freies Trijodthyronin (FT3) 4,6-9,2 pmol/l 66. TBG 12-30 gg/ml 67. Thyreoglobulin < 50 ng/ml 68. Transferrin 2,0-4,0g/l 69. Triglyzeride 0,83-2,3mmol/l 70. Vitamin A 0,7-2,8 µmol/l 71. Vitamin B12 229-812 pmol/l 72. Vitamin D 700-3100 U/l 73. Vitamin E 12-48 umol/l 74. Fragmentierte DNA, cfDNA 1-17 ng DNA/ml 75. Genomische DNA, gDNA < 2µg/ml 76. Extrazelluläre Vesikel 2 * 1010/mL 77. RNA 1-1000 ng/ml - Alle in einer wässrigen Lösung. Alle genannten Proteine werden auch Serum- oder Plasmaprotein genannt.
- In einer bevorzugten Ausführungsform ist die Zusammensetzung frei von Antikörpern, insbesondere frei von Immunglobulinen und / oder frei von DNA, RNA oder extrazellulären Vesikeln.
- Eine solche bereitgestellte Blutprobe wird nachstehend erfindungsgemäßes Referenzmaterial genannt.
- In einer weiteren bevorzugten Ausführungsform weist das hinzugegebene Blutplasma oder Blutserum definierte Werte an mindestens einem Inhaltsstoff auf, ausgewählt aus der Gruppe gDNA, fragmentierte DNA, tumorassoziiert und nicht tumorassoziiert, methylierte oder nicht methylierte cfDNA, histongebundene DNA, zirkuläre DNA, mitochondriale DNA, einzelsträngige oder doppelsträngige DNA, ctDNA, RNA, methylierte oder nicht methylierte RNA, miRMA, tRNA, scRNA, rRNA, mRNA, Tumornukleinsäure, gespikte Nukleinsäure, Exosom, Proteine, Peptide, extrazelluläre Vesikel, Exosomen, insbesondere mit den folgenden Bereichen 1-1500 ng DNA/ml, insbesondere mit einem Anteil an cfDNA bei Schwangeren von 2-15 % an fetaler cfDNA, 1-1000 ng RNA/ml.
- Weiterhin weist das hinzugegebene Blutplasma oder Blutserum definierte Werte an mindestens einem biologischen Material auf, ausgewählt aus der Gruppe Zellen, eukaryotische Zellen Viren, Pilze, Pilzsporen, Prionen, Bakterien, Parasiten, Tumorzellen, zirkulierende Tumorzellen (CTC), zirkulierende Endothelzellen (CTEC), insbesondere mit den folgenden Bereichen 1-100.000 Viren/ml, 1-100.000 Bakterien/ml, 1-100.000 Pilzen/ml, 1-100.000 Pilzsporen/ml, 1-100.000 Parasiten/ml, 1-1.000 Tumorzellen/ml oder 1-1.000 Endothelzellen/ml.
- Die vorgenannten Ausführungsformen des erfindungsgemäßen Referenzmaterials erlauben vorteilhaft die Simulation von Blutproben von beispielsweise kranken Patienten und anderen Zuständen.
- Weiterhin ist bevorzugt, dass fragmentierte (zellfreie) DNA (cfDNA), die in verschiedenen Größen vorkommen kann, bevorzugt in den Größenbereichen 140-180 Basenpaare (bp), 310-350 bp, 480-520 bp verwendet wird. Die Erfinder konnten feststellen, dass gerade für Sequenzierverfahren von Nukleinsäuren die Größe als auch Größenverteilung solcher cfDNA in einem Referenzmaterial kritisch ist.
- In einer weiteren Ausführungsform der Erfindung können große cfDNA Fragmente vorzugsweise in einer Größenordnung von 2.000 bis 15.000 bp verwendet werden, während mitochondriale DNA zwischen 40-300bp verwendet wird. Extrachromosomale zirkuläre DNA weist eine Größe zwischen 30-20.000 bp auf.
- Weiterhin ist bevorzugt, dass RNA, insbesondere miRNA, die in verschiedenen Größen vorkommen kann, bevorzugt in den Größenbereichen 10-250 bp, insbesondere 10-500 bp verwendet wird. Die Erfinder konnten feststellen, dass gerade für Sequenzierverfahren von Nukleinsäuren die Größe als auch Größenverteilung solcher RNA, insbesondere miRNA in einem Referenzmaterial kritisch ist.
- "Blut" im Sinne dieser Erfindung kann Vollblut sein, welche Blutzellen und Blutserum aufweisen. Insbesondere kann das Blut einem Menschen oder einem Tier entnommen werden.
- "Blutzellen" sind im Sinne dieser Erfindung solche, die nach Abtrennen des Blutserums zum Beispiel nach Zentrifugation im Rückstand verbleiben und Erythrozyten, Leukozyten, Thrombozyten u.a. umfassen.
- In einer bevorzugten Ausführungsform der Erfindung beträgt der Anteil an Blutzellen 15 - 70 Gew. %, vorzugsweise 37 - 54 Gew. % an dem erfindungsgemäßen Referenzmaterial.
- Weiterhin ist bevorzugt an dem erfindungsgemäßen Referenzmaterial, dass 99 Gew. % Erythrozyten (4,5 - 5,9 x 10^6 Zellen/ µl Blut sind, wobei der unterste Wert für Frauen und der oberste Wert für Männer gilt.
- Weiterhin ist bevorzugt an dem erfindungsgemäßen Referenzmaterial, dass < 1 % Leukozyten (ca. 4.000 - 10.000 Zellen / µl Blut für Erwachsene und für Kinder: bis zu 17.000 Zellen / µl Blut, Säuglinge bis zu 30.000 Zellen / µl Blut) und < 1 % Thrombozyten (ca. 150.000 - 400.000 Zellen/ µl Blut) .
- "Blutplasma" im Sinne dieser Erfindung ist durch Zentrifugieren von Blut und Abtrennen des Überstandes erhältlich, wobei das Blut zuvor mit einem Gerinnungshemmer, wie zum Beispiel Natriumcitrat oder EDTA versetzt wurde. Das Blutplasma enthält zumeist alle Gerinnungs- und Fibrinolysefaktoren in aktiver Form, sowie die cfDNA, die insbesondere bei der Anwendung der Flüssigkeitsbiopsietests weiter analysiert wird.
- "Blutserum" im Sinne dieser Erfindung ist durch Zentrifugieren von Blut und Abtrennen des Überstandes erhältlich. Im Unterschied zum Blutplasma sind keine Gerinnungshemmer enthalten.
- Im Sinne dieser Erfindung kann ebenfalls Blutserum oder Blutplasma verwendet werden, insbesondere solche welche im Wesentlichen folgende Bestandteile aufweisen:
Tabelle 2: Beispiel einer Zusammensetzung und Konzentrationen der Inhaltsstoffe eines erfindungsgemäßen Serums oder Plasmas (Lösungsmittel ist Wasser) Stoffname / Blutbestandteil Konzentration Plasmaproteine, insb. Albumin 50,3 g/l Elektrolyte (Na+) 89,6 mmol/l Elektrolyte (K+) 2,0 mmol/l Elektrolyte (Ca+) 0,025 mmol/l Elektrolyte (Cl-) 105,8 mmol/l Elektrolyte (PO4 3-) 6,7 mmol/l Tabelle 3: Beispiel einer Zusammensetzung und Konzentrationen der Inhaltsstoffe eines erfindungsgemäßen Serums oder Plasmas mit Zugabe von Stabilisatoren (Lösungsmittel ist Wasser) Stoffname Konzentration Plasmaproteine, insb. Albumin 50,3 g/l Elektrolyte (Na+) 89,6 mmol/l Elektrolyte (K+) 2,0 mmol/l Elektrolyte (Ca+) 0,025 mmol/l Elektrolyte (Cl-) 105,8 mmol/l Elektrolyte (PO4 3-) 6,7 mmol/l Organische Säuren (Citrat) 0,008 mmol/l EDTA 9,7183 mmol/l Tabelle 4: Beispiel einer Zusammensetzung und Konzentrationen der Inhaltsstoffe eines erfindungsgemäßen Serums oder Plasmas mit Zugabe von Stabilisatoren und zugegebenem Inhaltsstoff, welcher einem Analyten entspricht (Lösungsmittel ist Wasser) Stoffname Konzentration Plasmaproteine (z.B. Albumin) 50,3 g/l Elektrolyte (Na+) 89,6 mmol/l Elektrolyte (K+) 2,0 mmol/l Elektrolyte (Ca+) 0,025 mmol/l Elektrolyte (Cl-) 105,8 mmol/l Elektrolyte (PO4 3-) 6,7 mmol/l Organische Säuren (Citrat) 0,008 mmol/l EDTA 9,7183 mmol/l Fragmentierte DNA 80 ng DNA/ml Extrazelluläre Vesikel 2 * 1010/mL RNA 1000 ng/ml Viren 1000/ml Pilzsporen 1000/ml Bakterien 1000/ml Genomische DNA - In einer weiteren Ausführungsform kann daher zu dem erfindungsgemäßen Referenzmaterial eine oder mehrere chemische Substanzen hinzugefügt werden. Solche chemischen Substanzen können nicht abschließend sein, insbesondere mindestens ein organisches Molekül, welches neben Kohlenstoff (C) und Wasserstoff (H) Heteroatome enthalten kann, wie Sauerstoff (O), Stickstoff (N), Schwefel (S) oder Phosphor (P). Die chemischen Substanzen können lineare und/oder ringförmige Kohlenstoffketten samt Heteroatomen aufweisen. Bevorzugt sind organische Moleküle mit weniger als 1.000 g/mol. Eine solche chemische Substanz kann ein Biomarker, Analyt, Wirkstoff, Antikörper, Antigen oder Medikament sein. Insbesondere kann ein Inhaltsstoff hinzugefügt werden, ausgewählt aus der Gruppe gDNA, fragmentierte DNA, tumorassoziiert und nicht tumorassoziiert, methylierte oder nicht methylierte cfDNA, histongebundene DNA, zirkuläre DNA, mitochondriale DNA, einzelsträngige oder doppelsträngige DNA, ctDNA, RNA, methylierte oder nicht methylierte RNA, miRMA, tRNA, scRNA, rRNA, mRNA, Tumornukleinsäure, gespikte Nukleinsäure, Exosom, Proteine, Peptide, extrazelluläre Vesikel, Exosomen.
- In einer weiteren Ausführungsform kann zu dem erfindungsgemäßen Referenzmaterial ein oder mehrere biologische Materialien hinzugefügt werden, solche wie, ggfs. lebens- oder funktionsfähig, wie Zellen, eukaryotische Zellen Viren, Pilze, Pilzsporen, Prionen, Bakterien, Parasiten, Tumorzellen, zirkulierende Tumorzellen (CTC), zirkulierende Endothelzellen (CTEC).
- Im Sinne dieser Erfindung bedeutet "Tumornukleinsäure" eine beliebige und bekannte humane Wildtypsequenz. Solche Tumornukleinsäuren können Datenbanken, wie
- COSMIC: https://cancer.sanger.ac.uk/cosmic,
- Targeted Cancer Care: http://targetedcancercare.massgeneral.org/My-Trial-Guide/Diseases/Lung-Cancer/KRAS/G12C-(c-34G-T).aspx, oder
- OncoKB: https://oncokb.org/, My Cancer Genome:
- https://www.mycancergenome.org/, National Center for Biotechnology Information (NCBI)
- https://www.ncbi.nlm.nih.gov/gene/ entnommen werden.
- In einer bevorzugten Ausführungsform beträgt der Gehalt an einer Tumornukleinsäure, vorzugsweise 5 - 1000 ng, insbesondere 400 ng DNA in Serum oder Plasma, wie z.B. 400 ng/5ml, entspricht 80 ng/ml, entspricht 0,08 ng/µl DNA in Serum oder Plasma.
- Weiterhin ist bevorzugt, dass die Tumornukleinsäure eine Größe von 30 bp bis 500 bp aufweist.
- Im Sinne dieser Erfindung bedeutet "gespikte Nukleinsäure" eine solche Sequenz, die gegenüber einer humanen Wildtypsequenz einer Nukleinsäure ein oder mehrere Mutationen aufweist. Hierbei können gegenüber der humanen Wildtypsequenz bekannte Mutationssequenzen eingesetzt oder künstliche Mutationen eingeführt werden. Weiterhin ist bevorzugt, dass die gespikte Nukleinsäure mindestens einen Tumormarker, z.B. Onkogen, aufweist mit bekannten Mutationen, insbesondere ein Onkogen ausgewählt aus der Gruppe ABI1,ABL1,ABL2,ACKR3,ACSL3,ACVR1,ACVR2A,AFDN,AFF1,AFF3,AFF4,AK T1,AKT2,ALK,AMER1,APC,APOBEC3B,AR,ARHGAP26,ARHGEF12,ARID1A,ARI D1B,ARID2,ARNT,ASPSCR1,ASXL1,ATF1,ATIC,ATM,ATP1A1,ATP2B3,ATR,A TRX,AXIN1,AXIN2,B2M,BAP1,BARD1,BAX,BCL10,BCL11A,BCL11B,BCL2,BC L3,BCL6,BCL7A,BCL9,BCL9L,BCOR,BCORL1,BCR,BIRC3,BLM,BMPR1A,BRAF ,BRCA1,BRCA2,BRD3,BRD4,BRIP1,BTG1,BTK,BUB1B,CACNA1D,CALR,CAMTA 1,CANT1,CARD11,CARS,CASP8,CBFA2T3,CBFB,CBL,CBLB,CBLC,CCDC6,CCN B1IP1,CCND1,CCND2,CCND3,CCNE1,CD274,CD74,CD79A,CD79B,CDC73,CDH 1,CDH11,CDK12,CDK4,CDK6,CDKN1B,CDKN2A,CDKN2C,CDX2,CEBPA,CHCHD7 ,CHD4,CHEK2,CIC,CIITA,CLIP1,CLTC,CLTCL1,CNBP,CNOT3,CNTRL,COL1A 1,COL2A1,CREB1,CREB3L1,CREB3L2,CREBBP,CRLF2,CRTC1,CRTC3,CSF3R, CTCF,CTNNB1,CUX1,CXCR4,CYLD,DAXX,DCTN1,DDB2,DDIT3,DDR2,DDX10,D DX3X,DDX5,DDX6,DEK,DICER1,DNAJB1,DNM2,DNMT3A,DROSHA,EBF1,EGFR, EIF3E,EIF4A2,ELF4,ELK4,ELL,EML4,EP300,EPAS1,EPS15,ERBB2,ERBB3, ERBB4,ERC1,ERCC2,ERCC3,ERCC4,ERCC5,ERG,ESR1,ETNK1,ETV1,ETV4,ET V5,ETV6,EWSR1,EXT1,EXT2,EZH2,EZR,FANCA,FANCC,FANCD2,FANCE,FANC F,FANCG,FAS,FAT1,FAT4,FBXO11,FBXW7,FCGR2B,FCRL4,FES,FEV,FGFR1, FGFR1OP,FGFR2,FGFR3,FGFR4,FH,FHIT,FIP1L1,FLCN,FLI1,FLT3,FLT4,F OXA1,FOXL2,FOXO1,FOXO3,FOXO4,FOXP1,FSTL3,FUBP1,FUS,GAS7,GATA1, GATA2,GATA3,GNA11,GNAQ,GNAS,GOLGA5,GOPC,GPC3,GPHN,GRIN2A,H3F3A ,H3F3B,HERPUD1,HEY1,HIF1A,HIP1,HIST1H3B,HIST1H4I,HLA-A,HLF,HMGA1,HMGA2,HNF1A,HNRNPA2B1,HOOKS,HOXA11,HOXA13,HOXA9,HO XC11,HOXC13,HOXD11,HOXD13,HRAS,HSP90AA1,HSP90AB1,IDH1,IDH2,IGH ,IGK,IGL,IKBKB,IKZF1,IL2,IL21R,IL6ST,IL7R,IRF4,IRS4,ITK,JAK1,J AK2,JAK3,JUN,KAT6A,KAT6B,KCNJ5,KDM5A,KDM5C,KDM6A,KDR,KDSR,KEAP 1,KIF5B,KIT,KLF4,KLF6,KLK2,KMT2A,KMT2C,KMT2D,KNL1,KRAS,KTN1,LA SP1,LATS1,LATS2,LCK,LEF1,LIFR,LMNA,LMO1,LMO2,LPP,LRIG3,LRP1B,L YL1,LZTR1,MAF,MAFB,MALT1,MAML2,MAP2K1,MAP2K2,MAP2K4,MAP3K1,MAP 3K13,MAPK1,MAX,MDM2,MDM4,MECOM,MED12,MEN1,MET,MITF,MLF1,MLH1,M LLT1,MLLT10,MLLT11,MLLT3,MLLT6,MN1,MPL,MRTFA,MSH2,MSH6,MS12,MS N,MTCP1,MTOR,MUC1,MUTYH,MYB,MYC,MYCL,MYCN,MYD88,MYH11,MYH9,MYO 5A,MYOD1,NAB2,NBN,NCOA1,NCOA2,NCOA4,NCOR1,NCOR2,NDRG1,NF1,NF2, NFATC2,NFE2L2,NFIB,NFKB2,NFKBIE,NIN,NKX2-1, NONO,NOTCH1,NOTCH2,NPM1,NR4A3,NRAS,NRG1,NSD1,NSD2,NSD3,NT5C2,N TRK1,NTRK3,NUMA1,NUP214,NUP98,NUTM1,NUTM2B,NUTM2D,OLIG2,P2RY8, PAFAH1B2,PALB2,PATZ1,PAX3,PAX5,PAX7,PAX8,PBRM1,PBX1,PCM1,PDCD1 LG2,PDE4DIP,PDGFB,PDGFRA,PDGFRB,PER1,PHF6,PHOX2B,PICALM,PIK3CA ,PIK3CB,PIK3R1,PIM1,PLAG1,PLCG1,PML,PMS2,POLD1,POLE,POLQ,POT1, POU2AF1,POU5F1,PPARG,PPFIBP1,PPM1D,PPP2R1A,PPP6C,PRCC,PRDM1,PR DM16,PREX2,PRF1,PRKACA,PRKAR1A,PRRX1,PSIP1,PTCH1,PTEN,PTK6,PTP N11,PTPN13,PTPRB,PTPRC,PTPRK,PTPRT,QKI,RABEP1,RAC1,RAD21,RAD51 B,RAF1,RANBP2,RAP1GDS1,RARA,RB1,RBM10,RBM15,RECQL4,REL,RET,RHO A,RHOH,RMI2,RNF213,RNF43,ROS1,RPL10,RPL22,RPL5,RPN1,RSPO2,RSPO 3,RUNX1,RUNX1T1,SALL4,SBDS,SDC4,SDHA,SDHAF2,SDHB,SDHC,SDHD,SET ,SETBP1,SETD2,SF3B1,SFPQ,SFRP4,SH2B3,SH3GL1,SIX1,SLC34A2,SLC45 A3,SMAD2,SMAD3,SMAD4,SMARCA4,SMARCB1,SMARCD1,SMARCE1,SMO,SND1, SOCS1,SOX2,SPEN,SPOP,SRC,SRSF2,SRSF3,SS18,SS18L1,SSX1,SSX2,SSX 4,STAG2,STAT3,STAT5B,STAT6,STIL,STK11,STRN,SUFU,SUZ12,SYK,TAF1 5,TAL1,TAL2,TBL1XR1,TBX3,TCEA1,TCF12,TCF3,TCF7L2,TCL1A,TENT5C, TERT,TET1,TET2,TFE3,TFEB,TFG,TGFBR2,TLX1,TLX3,TMEM127,TMPRSS2, TNFAIP3,TNFRSF14,TNFRSF17,TOP1,TP53,TP63,TPM3,TPM4,TPR,TRA,TRA F7,TRB,TRD,TRIM24,TRIM27,TRIM33,TRIP11,TRRAP,TSC1,TSC2,TSHR,U2 AF1,UBR5,USP6,USP8,VHL,WAS,WDCP,WIF1,WRN,WT1,WWTR1,XPA,XPC,XPO 1,YWHAE,ZBTB16,ZFHX3,ZMYM2,ZNF331,ZNF384,ZNF521,ZRSR2,A1CF,ACS L6, AKAP9, AKT3, ALDH2, ANK1, ARAF, ARHGAP5, ARHGEF10, ARHGEF10L, ASXL2 ,BAZ1A, BCL2L12, BCLAF1, BIRC6, BMP5, C15orf65, CASP3, CASP9, CCNC, CCR 4, CCR7, CD209, CD28, CDH10, CDH17, CDKN1A, CEP89, CHD2, CHIC2, CHST11, C LP1,CNBD1,CNTNAP2,COL3A1,COX6C,CPEB3,CRNKL1,CSF1R,CSMD3,CTNNA2 , CTNND1, CTNND2, CUL3, CYP2C8, CYSLTR2, DCAF12L2, DCC, DGCR8, DUX4L1, E CT2L,EED,EIF1AX,ELF3,ELN,EPHA3,EPHA7,FAM131B,FAM135B,FAM47C,FA T3,FBLN2,FEN1,FKBP9,FLNA,FNBP1,FOXR1,GLI1,GMPS,GPC5,GRM3,HMGN2 P46, ID3, IGF2BP2, ISX, ITGAV, JAZF1, KAT7, KIAA1549, KNSTRN, LARP4B, LC P1, LEPROTL1, LHFPL6, LSM14A, MACC1, MALAT1, MB21D2, MDS2, MGMT, MNX1, M UC16,MUC4,N4BP2,NACA,NBEA,NCKIPSD,NTHL1,OMD,PABPC1,PCBP1,PMS1, POLG,PRDM2,PRKCB,PRPF40B,PTPN6,PTPRD,PWWP2A,RAD17,RALGDS,RFWD3 ,RGPD3, RGS7, R0B02, S100A7, SEPT5, SEPT6, SEPT9, SETD1B, SETDB1, SGK1, SHTN1,SIRPA,SIX2,SKI,SMC1A,SNX29,SOX21,SPECC1,SRGAP3,STAG1,TEC ,TFPT, TFRC, THRAP3, TNC, USP44, VAV1, VTI1A, WNK2, ZCCHC8, ZEB1, ZMYM3, ZNF429,ZNF479,ZNRF3.
- Weiterhin können solche Tumormarkersequenzen oder Onkogene weitere künstliche Mutationen aufweisen.
- Im Sinne dieser Erfindung bedeutet "Validierung", dass anhand des erfindungsgemäßen Referenzmaterials als Referenzprobe die bestimmungsgemäße Diagnostik, bzw. in-vitro Diagnostik durchgeführt wird, insbesondere zur Durchführung einer Kalibrierung unter Berücksichtigung der Geräteparameter oder zur Erstellung einer Eichkurve.
- In einer bevorzugten Ausführungsform der Erfindung ist die in-vitro Diagnostik eine Liquid Biopsy, wobei vorzugsweise mittels PCR aus einer Blutprobe gegen die erfindungsgemäße Blutprobe gemessen wird oder die erfindungsgemäße Blutprobe zur Kalibrierung, Validierung, der Diagnostik, oder in-vitro Diagnostik herangezogen wird.
- Überraschender Weise können auf diese Weise vorteilhaft bereits geringe Mengen an Probennukleinsäure z.B. aus einer Blutprobe mit hinreichender Spezifität und Sensitivität zu dem erfindungsgemäßen Referenzmaterial erfasst werden. Dies erlaubt im Fall einer Liquid Biopsy besonders vorteilhaft eine frühzeitige Aussage über die Tumoraktivität, insbesondere die Wahrscheinlichkeit einer Metastasierung. Eine bevorzugte Probennukleinsäure ist cfDNA oder ctDNA eines Patienten oder Probanden.
- Daher betrifft die Erfindung ebenfalls die vorteilhafte Verwendung des Referenzmaterials in einem Verfahren zur Bestimmung der Allelfrequenz und / oder Mutationsrate und/oder zur absoluten Quantifizierung mittels Kopienzahlbestimmung mindestens einer Probennukleinsäure mittels eines Sequenzierverfahrens für Nukleinsäuren. Besonders vorteilhaft kann anhand der Kalibrierung bzw. Validierung eine quantitative Bestimmung der Probennukleinsäure erfolgen.
- Weiterhin betrifft die Erfindung die vorteilhafte Verwendung des Referenzmaterials in einem Verfahren zur präanalytischen Evaluierung (Transport, Verarbeitung einer Blutprobe, Lagerung/Wiederholte Verwendung z.B. Gefrier-/Auftauzyklen, Extraktionsverfahren), analytischen Evaluierung (Genauigkeit / Präzision, Wiederholbarkeit / Reproduzierbarkeit, Analytische Spezifität / Sensitivität, Detektionslimit, Quantifizierungslimit, Leerwertgrenze, Linearität, Interferenz, Robustheit).
- Das Bereitstellen des erfindungsgemäßen Referenzmaterials erlaubt besonders vorteilhaft, die Nachweisgrenze der Probennukleinsäuren zu validieren. Eine besonders vorteilhafte Anwendung betrifft daher die Validierung von Geräten zur Durchführung einer Polymerase-Chain-Reaction (PCR), insbesondere next generation sequencing (NGS).
- Besonders vorteilhaft kann auf diese Weise eine exakt vorgegebene Menge an DNA-Material bzw. Konzentration in das erfindungsgemäße Referenzmaterial eingebracht werden, wobei dieses Referenzmaterial eine Patientenblutprobe simuliert und insbesondere für die Durchführung einer Tumordiagnostik, Schwangerschaftsdiagnostik, heriditäre genetische Diagnostik oder Infektionsdiagnostik hochgradig geeignet ist.
- "In-vitro Diagnose" im Sinne dieser Erfindung bedeutet jedwede Diagnose außerhalb des menschlichen oder tierischen Körpers (ex vivo) unter Bereitstellung geeigneter Assays und Geräte. Bevorzugt ist die Aussage über eine Krankheit oder einen Zustand eines Patienten.
- Im Rahmen dieser Erfindung wird unter "Patient" ein beliebiger Proband verstanden.
- Nachfolgend wird die Erfindung durch Beispiele erläutert. Die Erfindung ist jedoch nicht auf die Beispiele beschränkt, sondern grundsätzlich universell anwendbar.
- Die einzelnen Bestandteile aus Tabelle 1 können mit Blutzellen vermengt werden und auf diese Weise ein geeignetes Referenzmaterial bereitgestellt werden.
- Zugesetzte DNA in dem Referenzmaterial kann unter anderem wie folgt fragmentiert hinzugegeben werden, um die biologische Situation eines Menschen so nah wie möglich abbilden zu können.
Claims (14)
- Verwendung eines Referenzmaterials aufweisend Blut in einer Probe in einer in-vitro Diagnostik umfassend ein Sequenzierverfahren von Nukleinsäuren, wobei ein Stabilisator hinzugefügt wird.
- Verwendung eines Referenzmaterials aufweisend Blutzellen und Blutplasma oder Blutserum in einer Probe in einer in-vitro Diagnostik umfassend ein Sequenzierverfahren von Nukleinsäuren, wobei ein Stabilisator hinzugefügt wird.
- Verwendung eines Referenzmaterials aufweisend Blutzellen und Blutplasma oder Blutserum in einer Probe in einer in-vitro Diagnostik umfassend ein Sequenzierverfahren von Nukleinsäuren, wobei das Blutplasma oder Blutserum aus Albumin und 5 Bestandteilen oder bis zu 30 Bestandteilen der Tabelle 1 zusammengesetzt ist.
- Verwendung eines Referenzmaterials aufweisend Blutzellen und Blutplasma oder Blutserum in einer Probe in einer in-vitro Diagnostik umfassend ein Sequenzierverfahren von Nukleinsäuren, wobei das Blutplasma oder Blutserum aus Albumin und bis zu 76 Bestandteilen der Tabelle 1 zusammengesetzt ist.
- Verwendung eines Referenzmaterials aufweisend Blutzellen und Blutplasma oder Blutserum in einer Probe in einer in-vitro Diagnostik umfassend ein Sequenzierverfahren von Nukleinsäuren nach Anspruch 3 oder Anspruch 4, wobei das Blutplasma oder Blutserum nicht aus Menschen oder Tieren bereitgestellt wird.
- Verfahren zur Herstellung eines Referenzmaterials in einer Probe in einer in-vitro Diagnostik umfassend ein Sequenzierverfahren von Nukleinsäuren nach einem der Ansprüche 1 bis 5, wobei Blutplasma oder Blutserum zu Blutzellen hinzugegeben wird, und ein Stabilisator hinzugefügt wird.
- Verwendung oder Verfahren nach einem der vorherigen Ansprüche, wobei das Blutplasma oder Blutserum definierte Werte an Inhaltsstoffen und / oder biologischen Material aufweist.
- Verwendung oder Verfahren nach einem der vorherigen Ansprüche, wobei das Blutplasma oder Blutserum mindestens einen Inhaltsstoff aufweist, ausgewählt aus der Gruppe gDNA, fragmentierte DNA tumorassoziiert und nicht tumorassoziiert, methylierte oder nicht methylierte cfDNA, histongebundene DNA, zirkuläre DNA, mitochondriale DNA, einzelsträngige oder doppelsträngige DNA, ctDNA, RNA, methylierte oder nicht methylierte RNA, miRMA, tRNA, scRNA, rRNA, mRNA, Tumornukleinsäure, gespikte Nukleinsäure, Exosom, Proteine, Peptide, extrazelluläre Vesikel, Exosomen, insbesondere mit den folgenden Bereichen 1-1500 ng DNA/ml, insbesondere mit einem Anteil an cfDNA bei Schwangeren von 2-15 % an fetaler cfDNA, 1-1000 ng RNA/ml.
- Verwendung oder Verfahren nach einem der vorherigen Ansprüche, wobei das Blutplasma oder Blutserum mindestens ein biologisches Material aufweist, ausgewählt aus der Gruppe Zellen, eukaryotische Zellen Viren, Pilze, Pilzsporen, Prionen, Bakterien, Parasiten, Tumorzellen, zirkulierende Tumorzellen (CTC), zirkulierende Endothelzellen (CTEC), insbesondere mit den folgenden Bereichen 1-100.000 Viren/ml, 1-100.000 Bakterien/ml, 1-100.000 Pilzen/ml, 1-100.000 Pilzsporen/ml, 1-100.000 Parasiten/ml, 1-1.000 Tumorzellen/ml oder 1-1.000 Endothelzellen/ml.
- Verwendung oder Verfahren nach einem der vorherigen Ansprüche, wobei der Stabilisator ausgewählt wird aus der Gruppe bestehend aus vernetzenden Stabilisatoren, alkoholische Stabilisatoren und / oder Antikoagulanzien, insbesondere Formaldehyd, Glutaraldehyd, Glyoxal und Acrolein.
- Verwendung oder Verfahren nach einem der vorherigen Ansprüche, wobei mindestens eine weitere chemische Substanz und / oder mindestens ein biologisches Material hinzugefügt wird, insbesondere i.) Biomarker, Analyt, Wirkstoff, Antikörper, Antigen oder Medikament oder ii.) Zellen, eukaryotische Zellen Viren, Pilze, Pilzsporen, Prionen, Bakterien, Parasiten, Tumorzellen, zirkulierende Tumorzellen (CTC), zirkulierende Endothelzellen (CTEC).
- Verwendung oder Verfahren nach einem der vorherigen Ansprüche, dadurch gekennzeichnet, dass mithilfe des Referenzmaterials eine Validierungs- oder Kalibrierungskurve erstellt wird.
- Verwendung oder Verfahren nach einem der vorherigen Ansprüche, dadurch gekennzeichnet, dass das Sequenzierverfahren von Nukleinsäuren mittels PCR, qPCR (real-time quantitative Polymerase Chain Reaction), digital droplet PCR (ddPCR) oder "next generation sequencing" (NGS) durchgeführt wird.
- Verwendung oder Verfahren nach einem der vorherigen Ansprüche, dadurch gekennzeichnet, dass das Referenzmaterial eine Patientenblutprobe simuliert, insbesondere zur Durchführung einer Tumordiagnostik, Schwangerschaftsdiagnostik, heriditäre genetische Diagnostik oder Infektionsdiagnostik.
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EP21187066.2A EP4123033A1 (de) | 2021-07-21 | 2021-07-21 | Blutmatrix als referenzmaterial für die in-vitro diagnostik |
EP22754078.8A EP4373956A1 (de) | 2021-07-21 | 2022-07-21 | Blutmatrix als referenzmaterial für die in-vitro diagnostik |
JP2024503924A JP2024528707A (ja) | 2021-07-21 | 2022-07-21 | in‐vitro診断のための参照材料としての血液マトリックス |
CA3227039A CA3227039A1 (en) | 2021-07-21 | 2022-07-21 | Blood matrix as reference material for in-vitro diagnostics |
CN202280062145.7A CN118302537A (zh) | 2021-07-21 | 2022-07-21 | 作为用于体外诊断的参考材料的血液基质 |
PCT/EP2022/070560 WO2023001991A1 (de) | 2021-07-21 | 2022-07-21 | Blutmatrix als referenzmaterial für die in-vitro diagnostik |
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WO2012149188A2 (en) * | 2011-04-26 | 2012-11-01 | Longhorn Vaccines And Diagnostics, Llc | Compositions and methods for detecting and identifying nucleic acid sequences in biological samples |
US20170073738A1 (en) * | 2007-10-01 | 2017-03-16 | Longhorn Vaccines And Diagnostics, Llc | Compositions and Methods for Detecting and Quantifying Nucleic Acid Sequences in Blood Samples |
WO2017210372A1 (en) * | 2016-05-31 | 2017-12-07 | The Translational Genomics Research Institute | Molecular tagging methods and sequencing libraries |
WO2018094183A1 (en) | 2016-11-17 | 2018-05-24 | Seracare Life Sciences, Inc. | Methods for preparing dna reference material and controls |
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- 2022-07-21 CN CN202280062145.7A patent/CN118302537A/zh active Pending
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US20170073738A1 (en) * | 2007-10-01 | 2017-03-16 | Longhorn Vaccines And Diagnostics, Llc | Compositions and Methods for Detecting and Quantifying Nucleic Acid Sequences in Blood Samples |
WO2012149188A2 (en) * | 2011-04-26 | 2012-11-01 | Longhorn Vaccines And Diagnostics, Llc | Compositions and methods for detecting and identifying nucleic acid sequences in biological samples |
WO2017210372A1 (en) * | 2016-05-31 | 2017-12-07 | The Translational Genomics Research Institute | Molecular tagging methods and sequencing libraries |
WO2018094183A1 (en) | 2016-11-17 | 2018-05-24 | Seracare Life Sciences, Inc. | Methods for preparing dna reference material and controls |
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CA3227039A1 (en) | 2023-01-26 |
EP4373956A1 (de) | 2024-05-29 |
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